Portal hypertension is a disease state characterized by increased portal blood flow resistance and increased portal vein pressure due to occlusion or congestion of portal or hepatic venous system. Factors, which may contribute to the etiology of this state may be classified into pre sinusoidal and post sinusoidal conditions. The pre sinusoidal conditions include portal vein thrombosis, oriental schistosomiasis and Hodgkin's disease; and the post sinusoidal conditions include hepatocirrhosis, wedged hepatic venous occlusive disease and congestive heart disease.
The term "portal vein system" is a part of blood system wherein a vein or group of veins are branched to form a network of capillaries, and the capillaries then merge to form a vein or group of veins. In human beings, there are hepatic portal vein system and hypophyseal portal vein system, and in the hepatic portal vein system, splenic vein and superior and inferior mesenteric veins merge to form said system.
Prostaglandins (hereinafter, referred to as PG(s)) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or most other mammalian, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A): ##STR1##
On the other hand, some of synthetic analogues have a modified skeleton. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and named hereafter the existence or non-existence of an unsaturated bond or an oxidized group at the carbon chain moiety:
subscript 1: 13,14-unsaturated-15-OH PA1 subscript 2: 5,6- and 13,14-diunsaturated-15-OH PA1 subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH. PA1 A is --CH.sub.2 OH, --COCH.sub.2 OH, --COOH or a functional derivative thereof; PA1 B is --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH-- or --C.ident.C--; PA1 Q.sub.1 and Q.sub.2 are hydrogen, halogen or lower alkyl; PA1 R.sub.1 is bivalent saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, oxo or aryl; PA1 R.sub.2 is saturated or unsaturated, lower or medium aliphatic hydrocarbon residue which is unsubstituted or substituted with halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo lower alkyl, aryl or aryloxy.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position) into .alpha. type (the hydroxyl group is of an .alpha.-configuration) and .alpha. type (the hydroxyl group is of a .beta.-configuration).
In addition, some 15-keto (i.e. having an oxo group at position 15 in place of the hydroxy group) prostaglandins and 13,14-dihydro-15-keto-prostaglandins are known as substances naturally produced by enzymatic actions during metabolism of primary PGs. 15-keto PGs have been disclosed in, for example, EP-A-0281239 (corresponds to JP-A-104040/89), EP-A-0281480 (corresponds to JP-A-52753/89), EP-A0289349 (corresponds to JP-A-151552/89), and EP-A-0690049 (corresponds to JP-A-48665/96).
It is well known in the art that PG derivatives affect blood pressure. For example, PGE1, one of the primary PGs, has been known to have blood pressure decreasing activity, whereas 15-keto PGs have blood pressure increasing activity. However, the term "blood pressure" is generally used for "arterial blood pressure", and therefore, the effect of PGs, which have some activity in "arterial blood pressure", on pressure of portal vein system which consisting of venous vascular system is quite unpredictable.
As to the effects of PGs on portal vein pressure, PGE1 and PGE2, primary PGs, have been reported to have some effect. However, there are inconsistent evaluation among the reports such that increased, decreased and unchanged of the pressure due to the PGs were disclosed in the different reports. It has not been reported that how 15-keto-prostaglandin compounds affect portal vein pressure.